Utilize este identificador para referenciar este registo: https://hdl.handle.net/1822/62019

TítuloDisruption of amyloid precursor protein ubiquitination selectively increases amyloid β (Aβ) 40 levels via presenilin 2-mediated cleavage
Autor(es)Williamson, Rebecca L.
Laulagnier, Karine
Miranda, André M.
Fernandez, Marty A.
Wolfe, Michael S.
Sadoul, Rémy
Di Paolo, Gilbert
Palavras-chaveAmyloid beta-Peptides
Amyloid beta-Protein Precursor
Arginine
Cell Line
Endosomes
Humans
Lysine
Mutation
Peptide Fragments
Presenilin-2
Proteolysis
Ubiquitination
Alzheimer disease
amyloid precursor protein (APP)
amyloid- (A)
endosome
intracellular processing
intracellular trafficking
lysosome
presenilin
Data2017
EditoraAmerican Society for Biochemistry and Molecular Biology
RevistaJournal of Biological Chemistry
Resumo(s)Amyloid plaques, a neuropathological hallmark of Alzheimer's disease, are largely composed of amyloid β (Aβ) peptide, derived from cleavage of amyloid precursor protein (APP) by β- and γ-secretases. The endosome is increasingly recognized as an important crossroad for APP and these secretases, with major implications for APP processing and amyloidogenesis. Among various post-translational modifications affecting APP accumulation, ubiquitination of cytodomain lysines may represent a key signal controlling APP endosomal sorting. Here, we show that substitution of APP C-terminal lysines with arginine disrupts APP ubiquitination and that an increase in the number of substituted lysines tends to increase APP metabolism. An APP mutant lacking all C-terminal lysines underwent the most pronounced increase in processing, leading to accumulation of both secreted and intracellular Aβ40. Artificial APP ubiquitination with rapalog-mediated proximity inducers reduced Aβ40 generation. A lack of APP C-terminal lysines caused APP redistribution from endosomal intraluminal vesicles (ILVs) to the endosomal limiting membrane, with a subsequent decrease in APP C-terminal fragment (CTF) content in secreted exosomes, but had minimal effects on APP lysosomal degradation. Both the increases in secreted and intracellular Aβ40 were abolished by depletion of presenilin 2 (PSEN2), recently shown to be enriched on the endosomal limiting membrane compared with PSEN1. Our findings demonstrate that ubiquitin can act as a signal at five cytodomain-located lysines for endosomal sorting of APP. They further suggest that disruption of APP endosomal sorting reduces its sequestration in ILVs and results in PSEN2-mediated processing of a larger pool of APP-CTF on the endosomal membrane.
TipoArtigo
URIhttps://hdl.handle.net/1822/62019
DOI10.1074/jbc.M117.818138
ISSN0021-9258
e-ISSN1083-351X
Arbitragem científicayes
AcessoAcesso aberto
Aparece nas coleções:ICVS - Artigos em revistas internacionais / Papers in international journals

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